Hyperproliferative Skin Disorders and Diseases
Hyperproliferative skin disorders refers to a set of diseases and disorders, which are characterized by a higher than normal level of proliferation of epidermal cells known as keratinocytes, and, as a rule, also by abnormal differentiation.
The hyperproliferative epidermal pathology may be malignant or benign. Malignant hyperproliferative epidermal pathologies include: squamous-cell carcinoma (SCC), basal-cell carcinoma (BCC) and other non-melanoma skin cancers (NMSCs). Representative examples of benign hyperproliferative epidermal pathologies include psoriasis, common warts, keratoacanthoma, seborrhoeic keratosis, seborrhea and ichthyosis.
Psoriasis is a non-contagious skin disorder affecting up to 2% of the world's population. It is estimated that ten million in the U.S. and Europe suffer from psoriasis and up to 260,000 new cases are diagnosed each year. In the U.S. alone there are over 1,500,000 clinic visits per year for psoriasis and the annual outpatient costs are currently estimated to be about US $2 billion.
Psoriasis is caused by unknown factors that stimulate T-lymphocyte activation, proliferation, and cytokine release that leads to hyperproliferation of keratinocytes. Although the etiology of psoriasis is unknown, the affected keratinocytes are responsible for the typical clinical features of the disease: well-demarcated inflamed skin lesions covered with a silvery white scale, covering about 10%-15% of the body surface. Psoriasis primarily affects adults and may manifest itself in different variations and degrees of severity.
The main strategy for the treatment of hyperproliferative skin diseases, including psoriasis, is to prevent excessive keratinocyte division and to stimulate cell differentiation.
At present there are three modalities of treatment for psoriasis:
1) Topical administration of therapeutic cream or ointment, for treating mild and moderate cases;
2) Phototherapy (UVA or UVB) used alone or in combination with medication or topical treatment, requires repeated visits to the clinic and exposes the patient to the concomitant dangers of radiation;
3) Systemic treatment, relying on immunosuppressive therapy, is limited to severe cases due to the serious side effects.
Vitamin D and Hyperproliferative Skin Disease
Vitamin D is a prohormone with several active metabolites that act as hormones. In the skin, previtamin D3 is synthesized photochemically from 7-dehydrocholesterol and is slowly isomerized to vitamin D3, which is removed by vitamin D-binding protein. In the liver, vitamin D3 is converted to 25(OH)D3, the major circulating form, which passes through the enterohepatic circulation and is reabsorbed from the gut. In the kidneys, it is further hydroxylated to the more metabolically active form, 1α,25(OH)2D3 (1α,25-dihydroxycholecalciferol, calcitriol, vitamin D hormone).
Experimental evidence has shown that vitamin D functions as an anti-proliferative agent and stimulates the terminal differentiation of keratinocytes. In psoriatic lesions, epidermal keratinocytes exhibit hyperproliferation and impaired differentiation triggered by inflammation. Therefore, vitamin D and certain analogs are effective in treating psoriasis vulgaris (reviewed in DeLuca 1988; Lehmann et al., 2004). The systemic administration of these compounds is limited by their toxicity and adverse effect on calcium metabolism, therefore topical preparations are preferred.
Calcipotriol (calcipotriene), a vitamin D3 derivative is marketed in the United States as a topical antipsoriatic under the trade name Dovonex® (USA) or Daivonex® (Europe). Calcipotriol is as potent as the naturally occurring calcitriol in regulating cell proliferation, but has the benefit of being much less active in its effect on calcium metabolism. Despite this, calcipotriol is only partially effective in treating psoriatic lesions.
The art provides some examples of vitamin D analogs and derivatives and compositions comprising the same.
Vitamin D analogs are described in U.S. Pat. No. 4,851,401 (cyclopentano-vitamin D analogs), U.S. Pat. No. 5,120,722 (trihydroxycalciferol derivatives), U.S. Pat. No. 5,446,035 (20-methyl substituted vitamin D), U.S. Pat. No. 5,411,949 (23-oxa-derivatives), U.S. Pat. No. 5,237,110 (19-nor-vitamin D compounds), U.S. Pat. No. 4,857,518 (hydroxylated 24-homo-vitamin D derivatives). Additional Vitamin D analogs are taught in U.S. Pat. Nos. 4,804,502; 4,866,048; 5,145,846 5,374,629; 5,403,940; 5,446,034; and 5,447,924.
U.S. Pat. No. 5,037,816 is directed to a method of treating psoriasis which comprises topically administering an effective amount of a vitamin D compound which is capable of stimulating the differentiation of cultured tumor cells or normal rodent or human fibroblasts or keratinocytes in vitro.
U.S. Pat. No. 6,552,009 discloses a composition comprising a vitamin D analog and a derivative of retinoid useful in treating disorders characterized by abnormal cell-proliferation and/or cell-differentiation. In certain preferred embodiments the vitamin D analog is selected from calcitriol and calcipotriol.
U.S. Pat. No. 6,753,013 describes a pharmaceutical composition for dermal use comprising a combination of a vitamin D analog and a corticosteroid, the composition alleviating the inconvenience of a two-component regimen for the treatment of psoriasis and other inflammatory skin diseases.
Nicotinamide
Nicotinamide (NA, niacinamide), a derivative of vitamin B3 and a precursor of the coenzyme nicotinamide adenine dinucleotide (NAD), displays multiple functions in cell metabolism. NA has been shown to induce the differentiation of insulin-producing cells (Otonkoski et al, 1993) and the protection of the pancreatic beta-cells from genotoxic agents (Pipeleers and Van de Winkel, 1986). U.S. Pat. No. 6,248,763 relates to specific topical compositions for treating skin conditions for example acne and psoriasis, which comprise 0.01%-1% methyl nicotinate, as the active ingredient.
The synergistic effects of NA and vitamin D metabolites on differentiation and proliferation of human epidermal cells have recently been reported by some of the present inventors.
International Patent Application Publications WO 01/51051 and WO 2004/006887 of some of the present inventors are directed to compositions and methods of treating a benign or malignant hyperproliferative epidermal pathology comprising administering to the subject a therapeutically effective amount of an agent selected from the group consisting of nicotinamide and/or cyclic adenosine diphosphate-ribose (cADPR), and analogs thereof. The applications also disclose the combination of vitamin D3 metabolite (1α 25(OH2) D3) and NA and its synergistic effect on the differentiation and proliferation of human epidermal cells.
Vitamin D3 and vitamin D3 analogs are known to possess anti-proliferative and prodifferentiating properties and are therefore effective in the treatment of hyperproliferative skin disorders, for example psoriasis vulgaris. The synergistic effect of vitamin D3 with nicotinamide to further inhibit proliferation of keratinocytes has been demonstrated by some of the inventors of the present invention. Although a synergistic inhibitory effect of vitamin D3 and nicotinamide has been shown in keratinocytes in vitro, optimization of the two components in a pharmaceutical composition has never been shown.
The art has neither taught nor suggested specific formulations consisting essentially of a vitamin D3 analog and a nicotinamide analog for the prevention, treatment or attenuation of disorders associated with hyperproliferative skin diseases.
There remains a yet unmet medical need for compositions and methods useful in preventing and treating the symptoms associated with hyperproliferative disease, and in particular, psoriasis.